An Unexpected Tumor Reduction: Treatment with Olaparib Monotherapy in Heavily Pretreated BRCA2 Mutated Metastatic Pancreatic Cancer

Round 1

Reviewer 1 Report

1.Introduction mainly lacked the treatment progression of pancreatic cancer.
2.The patient has a history of breast cancer, and a biopsy pathological report was required to identify whether it from breast cancer metastasis；The patient was newly diagnosed with PDAC, and CT lesion size was not provided.
3.The histological examination confirmed the presence of scarcely differentiated PDAC pT2N2 stage III per TNM staging 8th edition. According to the guidelines, postoperative adjuvant chemotherapy was required, however, it was not mentioned in this paper.
4.Postoperative CT revealed lung metastasis, but it was not specified how long the metastasis was found after surgery. I would wonder if the lung metastases had existed before surgery.
5.Figure 2A displayed complete response on the lung metastases. However, it may still be residual lesions compared to Figure 1A; on the other hand, compared to Figure 2C and Figure 1C, pancreatic mass was reduced by 6mm, SD was evaluated according to RECIST 1.1, but the article said that” partial response was observed on the liver metastases and the peripancreatic tissue”.
6.“After the first two months of therapy, the patient displayed complete response on the lung metastases (Figure 2A); partial response was observed on the liver metastases and the peripancreatic tissue (Figure 2B, 2C). One single new liver lesion of uncertain origin was observed.” Was the new lesion observed during the 2-cycle assessment or later? If a new lesion was found during a two-cycle assessment, was the "liver lesion PR" credible?
7.Figure 3 can be added with corresponding pulmonary lesions for convenient comparison.

Author Response

1.Introduction mainly lacked the treatment progression of pancreatic cancer.
Thank you for your comment, I would really like to address it but admit I had issues with it. Would you mind to help me understanding better?
2. The patient has a history of breast cancer, and a biopsy pathological report was required to identify whether it from breast cancer metastasis；The patient was newly diagnosed with PDAC, and CT lesion size was not provided.
Thank you for this comment.
We specified into the “case description” section the pancreatic lesion size, together with the date of the CT scan (page 2 line 63-65).
3. The histological examination confirmed the presence of scarcely differentiated PDAC pT2N2 stage III per TNM staging 8th edition. According to the guidelines, postoperative adjuvant chemotherapy was required, however, it was not mentioned in this paper.
We agree with you on this observation: unfortunately, after surgery the patient developed a biliopancreatic fistula, which prolonged the hospitalization. Therefore, postoperative CT scan was performed almost two months after surgery. If the CT scan had not shown lung metastases, the patient would have received adjuvant chemotherapy. We specified it into the “case description” section page 2 line 68-70
4. Postoperative CT revealed lung metastasis, but it was not specified how long the metastasis was found after surgery. I would wonder if the lung metastases had existed before surgery.
Thank you for this observation.
We specified into the “case description” section that the preoperative CT scan did not detect any suspect pulmonary nodule (page 2 line 63-65).
5. Figure 2A displayed complete response on the lung metastases. However, it may still be residual lesions compared to Figure 1A; on the other hand, compared to Figure 2C and Figure 1C, pancreatic mass was reduced by 6mm, SD was evaluated according to RECIST 1.1, but the article said that” partial response was observed on the liver metastases and the peripancreatic tissue”.
Thank you for your observation.
The overall response observed at first re-evaluation was partial response since the difference between the sum of target lesions at baseline and at the first re-evaluation was > 30%. In fact, the sum of target lesions at baseline was 110, whereas it was 71 at the first re-evaluation. No residual pulmonary lesions were observed as confirmed also by our radiologists. However, in order to avoid confusion, we erased “on the liver metastases and the peripancreatic tissue” and specified that overall response was partial response (page 3 line 98).
6. “After the first two months of therapy, the patient displayed complete response on the lung metastases (Figure 2A); partial response was observed on the liver metastases and the peripancreatic tissue (Figure 2B, 2C). One single new liver lesion of uncertain origin was observed.” Was the new lesion observed during the 2-cycle assessment or later? If a new lesion was found during a two-cycle assessment, was the "liver lesion PR" credible?
Thank you for your comment.
The new liver lesion was of uncertain nature: given that it was no longer visible at the second re-evaluation CT scan, as we previously specified in page 3 line 105, it was not considered metastatic.
7. Figure 3 can be added with corresponding pulmonary lesions for convenient comparison.
Added, thank you

Reviewer 2 Report

Interesting case report, no major comment

however the report does not add further evidence to the PARP inhibitor use

Author Response

We thank the reviewer for this feedback.

Author Response File: Author Response.pdf

Reviewer 3 Report

The manuscript by Prete et al presented a case of a remarkable clinical and radiological response to olaparib in a heavily pretreated patient with BRCA2 germline mutation. The POLO trial showed that PARPi maintenance therapy can increase the PFS of those with BRCA mutant pancreatic cancer. Though some patients had intrinsic or acquired resistance, considering the impressive result of POLO trial, the FDA approved PARPi maintenance therapy for these patients. This case reinforced the importance of genetic testing guided precision therapy for these patients. Overall, the case report presented here is interesting. But the discussion section could be improved by addressing the following concerns.

1. The most recent NCCN guideline suggested genetic testing for all patients with pancreatic cancer. What’s the current status of genetic testing for patients with pancreatic cancer in Italy? Is it a routine test or is it only for those with high-risk tumors? Please add some discussion.
2. After 3-4 months of PARPi therapy, the metastatic lesions on lung and liver were invisible or reduced in size. Was the peripancreatic mass still unresectable or borderline resectable? If it was borderline resectable, did they consider more progressive treatment options, such as surgical resection of the peripancreatic mass and radiofrequency ablation (RFA) for the liver lesions?
3. Recent studies showed that those with BRCA2 mutation are more likely to benefit from immune checkpoint inhibitors (PMID: 33961040). Did they consider immunotherapy at that time when the tumor progressed after treating with PARPi for 6 months? Please add some discussion on this emerging field.
4. “Germline BRCA mutations are found in a small subgroup of patients, accounting for no more than 4% of PDAC.” Please add the reference.
5. Besides BRCA testing, did the patient receive any other genetic testing?
6. Was this patient tested for Lynch syndrome?
7. There are so many paragraphs in the section of discussion. Some paragraphs have only one sentence. Please reorganize the discussion.

Author Response

The manuscript by Prete et al presented a case of a remarkable clinical and radiological response to olaparib in a heavily pretreated patient with BRCA2 germline mutation. The POLO trial showed that PARPi maintenance therapy can increase the PFS of those with BRCA mutant pancreatic cancer. Though some patients had intrinsic or acquired resistance, considering the impressive result of POLO trial, the FDA approved PARPi maintenance therapy for these patients. This case reinforced the importance of genetic testing guided precision therapy for these patients. Overall, the case report presented here is interesting. But the discussion section could be improved by addressing the following concerns.

1. The most recent NCCN guideline suggested genetic testing for all patients with pancreatic cancer. What’s the current status of genetic testing for patients with pancreatic cancer in Italy? Is it a routine test or is it only for those with high-risk tumors? Please add some discussion.

Thank you for this important observation. A specific statement was made in the
“discussion” section, referring to the newest Italian guidelines and
recommendations about BRCA testing in pancreatic cancer (page 4-5 line 199-
214)

2. After 3-4 months of PARPi therapy, the metastatic lesions on lung and liver were invisible or reduced in size. Was the peripancreatic mass still unresectable or borderline resectable? If it was borderline resectable, did they consider more progressive treatment options, such as surgical resection of the peripancreatic mass and radiofrequency ablation (RFA) for the liver lesions?

After 3-4 months of PARPi therapy, the metastatic lung lesions were disappeared, but liver lesions were still present; the peripancreatic tissue was slightly reduced in size, but surgery was considered at high risk due to the previous surgery and the lesion size and position. Given extrapancreatic spread, the previous pancreatic surgery and the dimension of peripancreatic lesion, no surgical or locoregional approaches were deemed feasible.

3.Recent studies showed that those with BRCA2 mutation are more likely to benefit from immune checkpoint inhibitors (PMID: 33961040). Did they consider immunotherapy at that time when the tumor progressed after treating with PARPi for 6 months? Please add some discussion on this emerging field.

Thank you for this stimulating comment.
A paragraph regarding immunotherapy in PDAC and in particularly in BRCA2
mutated PDAC was added in the discussion section (page 6 line 326-341).
Unfortunately, in 2019 few data regarding immunotherapy in PDAC were
available; furthermore, our patient had an MSS tumor (data now added). For this
reason, given also the worsening clinical conditions, we did not consider
immunotherapy after PARPi.

4.“Germline BRCA mutations are found in a small subgroup of patients, accounting for no more than 4% of PDAC.” Please add the reference.

Done (page 4, line 191)

5.Besides BRCA testing, did the patient receive any other genetic testing?

Yes, microsatellite status was also assessed, resulting MSS (page 2, line 111-112)

6.Was this patient tested for Lynch syndrome?

Given the microsatellite status, the patient did not undergo Lynch syndrome
testing

7.There are so many paragraphs in the section of discussion. Some paragraphs have only one sentence. Please reorganize the discussion.

Thank you for this obstervation. Paragraphs were reorganized. Moreover, some
references were added to further update discussion bibliography.

Round 2

Reviewer 2 Report

Good review according to other reviewers' suggestions